Hydroxamic acid derivatives of 3-Phenyl propionic acids useful as therapeutic agents for treating anthrax poisoning

ABSTRACT

Compounds having the formula 
     
       
         
         
             
             
         
       
     
     wherein the symbols have the meaning described in the specification are hydroxamic acid derivatives of 3-phenyl-propionic acid and capable of inhibiting the lethal effects of infection by anthrax bacteria and are useful in the treatment of poisoning by anthrax.

CLAIM OF PRIORITY

The present application claims the priority of U.S. provisionalapplication Ser. No. 60/898,965 filed on Feb. 1, 2007.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant no.R44AI052587 awarded by the National Institutes of Health. The USgovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds useful for treatment ofpoisoning by bacillus anthracis (anthrax infection or poisoning). Moreparticularly, the invention is directed to compounds capable ofinhibiting the lethal effects of infection by anthrax bacteria and areuseful in the treatment of poisoning by anthrax. The compounds of theinvention are hydroxamic acid derivatives of 3-phenyl-propionic acid.

2. Background Art

Anthrax is a disease caused by infection of mammals, including humans,by bacillus anthracis. Spores of these bacteria can enter the mammalian,including human body, through skin abrasions, the digestive system orinhalation. Whereas anthrax poisoning in humans through skin abrasion orthe digestive system can often be treated with antibiotics, anthraxpoisoning in humans by ingestion of aerosol usually results in death ofthe infected individual.

Relatively recently, devices have been made which incorporate bacillusanthracis or its spores and are capable of releasing the bacteria or itsspores in aerosol form. This “weaponized” form of anthrax can serve as a“weapon of mass destruction” in biological warfare and is feared in theWestern World for its potential use by terrorists against civilianpopulations.

For all these reasons a serious effort has been made in the fields ofmedical and related biological research to elucidate the mode and agentof poisoning by bacillus anthracis and efforts have been made tosynthesize compounds which act as inhibitors of the lethal toxins andtherefore can treat the infection.

The following scientific publications describe or relate to the mannerof infection by the bacteria and to elucidation of the toxic factors andtheir mode of action in the mammalian, including human body: Dixon etal. (1999) N. England J. Med. 341. 815-26; Mock et al. Annu. Rev.Microbiol. 55. 647-71; Vitalae et al. (1998) Biochem. Biopphys. Res.Commun. 248, 706-11; Vitalae et al. (2000) Biochem J. 352 Pt 3, 739-45;Duesbery et al. (1998) Science 280. 734-7; Duesbery et al. InternationalPublication No. WO 99/50439; Hammond et al. (1998) Infect. Immun. 66,2374-8. A summary of these findings is that the toxin, called “lethalfactor”, released by bacillus anthraci is an enzyme that splits anessential peptide needed by mammalian organisms for signal transmission.Thus, inhibitors of this bacterial enzyme are candidates for drugs fortreatment of anthrax poisoning.

Published US Patent Application No. 2005/0148629 (Jul. 7, 2005)describes hydroxamic acid compounds which have the general formula shownbelow

where the R¹ is aryl, or heteroaryl, or heterocyclic and where Rrepresents a large number of potential substituents, including alkyl,and which can be used in the treatment of anthrax poisoning.

Published International Application WO 2005/027856 (Mar. 31, 2005)describes numerous compounds said to be inhibitors of anthrax lethalfactor.

Published International Application WO 97/24117 discloses compounds ofthe general formula

including some examples where the variable p=1, q=0 and m=1. Saidcompounds are said to be inhibitors of cyclic AMP phosphodiesterase.

Published European Patent Application EP 1 707 560 A1 includes formulas1 through 10 (pages 1-15) which purport to cover a very large number ofcompounds of diverging structures, some of which are pertinent to thecompounds of the present invention.

The present invention represents a further advance in the field byproviding hydroxamic acid derivatives of phenyl-propionic acid which areuseful to treat anthrax poisoning.

SUMMARY OF THE INVENTION

The present invention relates to compounds of Formula 1

where

R¹ is F, Cl, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons,thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF₃, OCF₃; OH, NH₂,NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CO₂H or CO₂(C₁-C₆ alkyl);

m is an integer having the value of 1 to 3;

R² is alkyl of 1-9 carbons; C₁-C₆ alkylphenyl where phenyl issubstituted with 0-3 R¹ groups, C₁-C₆ alkylcyclohexyl, (CH₂)_(n)OR³,(CH₂)_(n)NHR⁴, NR⁴C₁-C₆alkyl, (CH₂)_(n)CF₃, CH₂OCH₂-phenyl;

(CH₂)_(n)NH(CH₂)_(n)R⁴, (CH₂)_(n)NR⁶R⁴, (CH₂)_(n)NR⁶(CH₂)_(n)R⁴,(CH₂)_(n)O(CH₂)_(n)R⁴, (CH₂)_(n)OR⁴, CN, phenyl substituted with 0 to 3R¹ groups, an alkenyl group having 2 to 9 carbons and one double bond,

n is an integer having the value of 1 to 8;

R³ is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1to 6 carbons and the phenyl is substituted with 0-3 R¹ groups;

R⁴ is H, alkyl of 1 to 10 carbons, (CH₂)_(p)cyclohexyl, C(O)alkyl of 1to 4 carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbonsand the phenyl is substituted with 0-3 R¹ groups or with a 5 to 6membered heteroayl group having 1 to 2 heteroatoms selected from O, S,and N, or with a 5 to 6 membered heteroaryl group having 1 to 2heteroatoms selected from O, S and N and condensed with a phenylgroup,said heteroaryl or condensed heteroaryl group itself substituted with0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)COOH, (CH₂)_(p)phenyl where thephenyl is substituted with 0-3 R¹ groups or with a NO₂ group, or R⁴ isC(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl where the phenyl is substitutedwith 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups, or R⁴ is C(O)CH(Ph)₂,C(O)—CH₂-(3PhO—)Ph, or R⁴ is a 5 to 6 membered heteroaryl group having 1to 2 heteroatoms selected from O, S, and N, or a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenyl group, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is CH₂heteroaryl**CH₂heteroaryl condensed with phenyl where the heteroaryl group is 5 or6 membered and has 1 to 2 heteroatoms selected from O, S said heteroarylgroup or condensed heteroaryl itself substituted with 0-3 R¹ groups, orR⁴ is SO₂-alkyl of 1 to 6 carbons, SO₂-Ph where the phenyl issubstituted with 0-3 R¹ groups or with NO₂ or with COOR⁵ group, or R⁴ isC(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkyl group has 1 to 4carbons and where the phenyl is substituted with 0-3 R¹ groups;

-   -   p is an integer having the value of 0 to 4;    -   R⁵ is alkyl of 1 to 6 carbons or phenyl substituted with 0-3 R¹        groups or with an OPh group;    -   R⁶ is alkyl of 1 to 6 carbons;        the star indicates an asymmetric carbon, the wavy line        represents a bond that can be in the R or in the S        configuration,        or a pharmaceutically acceptable salt of said compound,

with the proviso that compounds selected from the group consisting ofcompounds identified below with structural formulas

are not included in the invention as novel composition of matter.

The present invention also relates to pharmaceutical compositionssuitable for administration to mammals, including humans, which includeone or more compounds of the invention and are used for treatment orprevention of anthrax poisoning.

Biological Activity, Modes of Administration Determining BiologicalActivity

As briefly noted above in the introductory section of this applicationfor patent, the most serious, often lethal results of anthrax poisoningare caused by a toxin that is released by bacillus anthracis within thehost. The toxin includes three proteins, one of which is azinc-dependent metalloprotease enzyme (lethal factor) that cleaves nearthe N termini of several MAP kinase kinase enzymes (MKKS) of the host.It is this disruption of key signaling pathways mediated by the host MKKenzymes that result in the severe and often lethal results of infectionby the bacteria.

An assay for identifying and measuring the effectiveness of potentialdrugs to treat anthrax poisoning is based on measuring the inhibitoryeffect of the candidate compound on the lethal factor enzyme. Theprocedure used in the present invention to measure the potentialefficiency of the compounds of the present invention is based, in asomewhat modified form, on the assay described by Cummings et al., Apeptide-based fluorescence resonance energy transfer assay for Bacillusanthracis lethal factor protease, PNAS, May 14, 2002, Vol 99, No. 106603-6606, expressly incorporated herein by reference. The gist of thisassay that a fluorogenic peptide substrate is incubated with the lethalfactor enzyme in the presence of the inhibitor and the inhibition of thelethal factor is measured by measuring the fluorescence intensity of thecleaved substrate. A description of the actual assay conditions used forevaluating the compounds of the present invention is provided below.

Assay Procedure

Inhibitors were solubilized in 100% DMSO at 10 mM, then diluted to thefinal desired concentration and 10% final DMSO in the assay. Lethalfactor protease (20 nM) and inhibitor were briefly incubated at roomtemperature in the assay buffer (20 mM Hepes, 0.05% Tween 20, 0.02%NaN₃, pH 7.4), and the reaction started by the addition of 12.5 μM finalof the fluorogenic peptide substrate, MAPKKide™ (List BiologicalLaboratories, Inc, Campbell, Calif.). The final volume was 50 μL, inhalf area black microtiter plates (Costar). Fluorescence intensity (Ex:320 nm, Em: 420 nm) was monitored for 15 minutes at room temperature(Gemini XS, Molecular Devices), and the K_(i) ^(app) values werecalculated using the program BatchKi (BioKin Ltd., Pullman, Wash.).Generally speaking a compound is considered active in this assay if thecalculated K_(i) ^(app) value is less than 300 (<300) μM.

Modes of Administration

The compounds of the invention are useful for treating anthraxpoisoning. The compounds of this invention may be administeredsystemically through oral, intravenous or other modes of systemicadministration, depending on such considerations as the severity of theanthrax infection treated, quantity of drug to be administered, andnumerous other considerations. For oral administration the drug may beconfected as a powder, pill, tablet or the like or as a syrup or elixirsuitable for oral administration. For intravenous or intraperitonealadministration, the compound will be prepared as a solution orsuspension capable of being administered by injection. In certain cases,it may be useful to formulate the compounds of the invention insuppository form or as extended release formulation for deposit underthe skin or intramuscular injection. For each type of administrationappropriate pharmaceutical excipients are likely to be added to thedrug. The nature of such excipients for each type of systemicadministration is well known in the art and need not be described herefurther.

A useful therapeutic or prophylactic concentration will vary from withthe precise identity of the drug, with the severity of the anthraxinfection being treated and the patient's susceptibility to treatment.Accordingly, no single concentration will be uniformly useful, but willrequire modification depending on the particularities of each situation.However, it is anticipated that an amount between 0.1 and 10 mg per kgof body weight per day will affect a therapeutic result.

Results of the Assay Measuring Lethal Factor Inhibitory Activity

Specific examples of compounds within the scope of the present inventionare shown by their respective structural formulas in Tables 1 through 4and their activity in the above-described assay is also indicated.

TABLE 1

 Compound #  Ar$\frac{{LF}\mspace{11mu} ({FRET})}{\left. {K_{i}^{app}\; {\mu M}} \right)}$167550 Ph- 65.2 167266 3-Me-4-F-Ph- 2.3 167533 3,5-diMe-4-F-Ph- 1.2

TABLE 2

 Compound #  R²$\frac{{LF}\mspace{11mu} ({FRET})}{\left. {K_{i}^{app}\; {\mu M}} \right)}$167857 —H 1.34 167858 (R,S)-Me 0.40 167914 (R,S)-CN 47.5 167856 (R,S)4-Br-Ph 0.62 168009 (R) 4-Br-Ph 0.77 167973 (S) 4-Br-Ph 5.7 168051(R)-(E)-(CH₂)₃CH═CH-iPr 51.6 168052 (R)-(CH₂)₅-iPr 300 168023(S)-(E)-(CH₂)₃CH═CH-iPr 1.97 168031 (S)-(CH₂)₅-iPr 2.66

TABLE 3

 Compound #  R¹  R²$\frac{{LF}\mspace{11mu} ({FRET})}{\left. {K_{i}^{app}\; {\mu M}} \right)}$168171 Me —NH-(2-propyl-pentyl) 0.25 168170 Me —NH—CH₂-cyclohexyl 0.40168149 Me —NH—CH₂-Ph 0.13 168132 Me —NH-(4-F-Ph) 2.24 168139 H—NH—CH₂-(3-Me-4-F-Ph) 0.28 168050 Me —NH—CH₂-(3-Me-4-F-Ph) 0.074 168117Me —NH—CH₂-(4-F-Ph) 0.045 168122 Me —NH—(CH₂)₂-(4-F-Ph) 0.065 168123 Me—NH—(CH₂)₃-(4-F-Ph) 0.047 168125 Me —NH—CH₂-(4-Cl-Ph) 0.19 168140 H—NH—CH₂-(3-Ph-Ph) 0.70 168141 Me —O—CH₂-(3-Me-4-F-Ph) 3.60 168126 Me—N(Me)—CH₂-(4-F-Ph) 0.55 168124 Me —(CH₂)₂-(4-F-Ph) 10.3 168148 Me—NH—CH₂-5-(benzo[1,3]dioxolyl) 0.22 168157 Me—NH—CH₂-2-(5-methylfuranyl) 0.13 168179 Me —NH—CH₂-2-pyrazinyl 0.71168180 Me —NH—CH₂-2-benzo[b]thienyl 0.40

TABLE 4

 PT  R¹  R²$\frac{{LF}\mspace{11mu} ({FRET})}{\left. {K_{i}^{app}\; {\mu M}} \right)}$168150 4-Cl (S) —(CH₂)₂N(Me)—(CH₂)₃-(3-Me-4-F-Ph) 1.75 168156 4-Cl (S)—(CH₂)₂N(Me)—(CH₂)₃-(3,5-diMe-4-F-Ph) 3.29 168134 4-Cl (S)—(CH₂)₆-(3-Me-4-F-Ph) 64.5 168164 3-Cl, 4-F (S)—(CH₂)₄—N(Me)—CH₂-(4-F-Ph) 0.20 168172 3,5-diMe, 4-F (S)—(CH₂)₂N(Me)—(CH₂)₃-(4-F-Ph) 0.29

GENERAL EMBODIMENTS AND SYNTHETIC METHODOLOGY Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl and branched-chain alkyl. Unless specified otherwise,lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and 3 to 6 carbonsfor lower branch chained alkyl groups. A pharmaceutically acceptablesalt may be prepared for any compound used in accordance with theinvention having a functionality capable of forming a salt, for examplean acid or an amino functionality. A pharmaceutically acceptable salt isany salt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids. Preferred salts are those formed with inorganic acids such ashydrochloric acid, sulfuric acid or phosphoric acid. Any of a number ofsimple organic acids such as mono-, di- or tri-acid may also be used.

Some compounds used in accordance with the present invention may havetrans and cis (E and Z) isomers. Unless specific orientation ofsubstituents relative to a double bond or a ring is indicated in thename of the respective compound, and/or by specifically showing in thestructural formula the orientation of the substituents relative to thedouble bond or ring the invention covers trans as well as cis isomers.

Some of the compounds used in accordance with the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all isomers per se, as well as mixturesof cis and trans isomers, mixtures of diastereomers, pure enantiomers(optical isomers) and 50:50 (racemic) or other ratio mixtures ofenantiomers as well. In some cases one compound of a diastereomericspecies, or one specific enantiomer of a chiral compound is more activethan the other diastereomer(s) or optical isomer, and when such a caseis established it is indicated in the respective designation of thecompound.

General Synthetic Methodology

The novel compounds used in accordance with the invention areencompassed by the general Formula 1 provided above.

A general route for the synthesis of the compounds of Formula 1 is shownin the General Scheme 1, below.

Referring now to General Scheme 1 a derivative of malonic acid and asubstituted benzaldehyde serve as starting materials. The variables R¹,m and R² are as defined in Formula 1. Such starting materials are eitheravailable commercially or can be obtained in accordance with knownchemical scientific and or patent literature or by such modifications ofknown synthetic procedures which will be readily apparent to thoseskilled in the art. The malonic acid derivative and the substitutedbenzaldehyde are reacted in a suitable solvent, such as a mixture ofpiperidine and pyridine to give the compound shown in the scheme asIntermediate Formula 1. The olefinic double bond in the latter compoundis saturated by hydrogenation to give the compound shown as IntermediateFormula 2. Intermediate Formula 2 is then reacted withO-(tetrahydropyran-2-yl)-hydroxylamine in the presence of1-hydroxybenzotriazole (HOBt) and N-methylmorpholine (NMM) to give thecompound of Intermediate Formula 3. The tetrahydropyranyl group isremoved from Intermediate Formula 3 by treatment with trifluoroaceticacid (TFA) in a suitable aprotic solvent, such as dichloromethane (DCM)to give the compounds of Formula 1.

General Synthetic Scheme 2 discloses a synthetic route to a particularclass of compounds of the invention which are shown in Tables 1 and 2.The starting materials in this scheme is a triphenylphosphine compounds(Wittig reagent) that can be obtained in accordance with well knownsynthetic procedures from compounds that are themselves readilyavailable commercially or from the chemical literature. Thetriphenylphosphosphine compound is reacted with a benzaldehydesubstituted with 0 to 3 (R¹)_(m) groups to provide the IntermediateFormula 4 in a suitable solvent, such as THF and with heating. Thevariable symbols n, m and R¹ are defined as in connection withFormula 1. The Intermediate Formula 4 is then subjected to catalytichydrogenation in methanol to give Intermediate Formula 5. TheIntermediate Formula 5 is subjected to treatment with potassium cyanide(KCN) and hydroxylamine (NH₂OH—H₂O) in the presence of a suitablesolvent or solvent mixture, such as tetrahydrofuran (THF) and methanol(MeOH) to provide compounds of Formula 2. The compounds of Formula 2represent a subgenus of the compounds of Formula 1.

General Scheme 3 discloses a synthetic route to another particular classof compounds of the invention which are shown in Table 2 and wherein theR² group with reference to Formula 1 is (CH₂)_(n)NHR⁴ and where R⁴ is(CH₂)_(p)phenyl with the phenyl substituted with 0 to 3 R¹ groups. Thevariable symbols in General Scheme 3 have the same meaning as inconnection with Formula 1. Unless otherwise indicated this is generallytrue in the descriptions of all of the general schemes. The startingmaterial in this scheme is an alkenoic acid chloride that is readilyavailable commercially or from the chemical literature. The alkenoicacid chloride is reacted with (R)-4-benzyloxazolidin-2-one (commerciallyavailable) in the presence of butyl lithium and in a suitable solvent orsolvent mixture, such as THF and hexane to give the Intermediate Formula6. The Intermediate Formula 6 is then reacted with a substituted benzylbromide in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) inTHF to yield the Intermediate Formula 7. The olefinic bond of theIntermediate Formula 7 is oxidized and converted into an aldehydefunction by treatment with ozone, followed by decomposition of theintermediate ozonide by treatment with dimethylsulfide (Me₂S) indichloromethane to provide Intermediate Formula 8. The IntermediateFormula 8 is made into a Shiff base with phenylalkylamine shown in thescheme, and the Schiff base is reduced to provide the IntermediateFormula 9.

The Intermediate Formula 9 is converted to the hydroxamic acid compoundof Formula 3 by treatment with potassium cyanide (KCN) and hydroxylamine(NH₂OH—H₂O) in the presence of a suitable solvent or solvent mixture,such as tetrahydrofuran (THF) and methanol (MeOH). The compounds ofFormula 3 are within the scope of the invention and represent a subgenusof the compounds of Formula 1.

Specific Scheme 6 below discloses a method of preparing[3-(4-fluoro-phenyl)-propyl]-methyl-amine that serves as intermediate(C6) in the preparation of a compound that itself is made in accordancewith the procedure disclosed in General Scheme 3. A person havingordinary skill in the art can readily modify the specific procedure ofsynthesizing intermediate C6 to make other intermediates of likestructure to be used for the synthesis of compounds of the invention asdisclosed in General Scheme 3.

General Scheme 4 discloses a synthetic route to still another particularclass of compounds of the invention which are shown in Table 2 andwherein the R² group with reference to Formula 1 is (CH₂)_(n)OR⁴ andwhere R⁴ is (CH₂)_(p)phenyl with the phenyl substituted with 0 to 3 R¹groups. One starting material in this scheme is a lactone of an omegahydroxyl alkanoic acid. The variable n for this starting material hasthe same definition as in connection with Formula 1 with the restrictionthat the starting material must be able to form a cyclic lactone. Theother starting material is a substituted phenylalkylbromide where thevariables R¹, p and m have the same definition as in connection withFormula 1. These starting materials are reacted in the presence ofstrong base, such as KOH in a suitable solvent, such as toluene toprovide the Intermediate of Formula 10. The Intermediate of Formula 10is then reacted with (R)-4-benzyloxazolidin-2-one in the presence oftriethylamine, pivaloyl chloride and LiCl in an aprotic solvent, such asTHF, to give the Intermediate Formula 11. The Intermediate Formula 11 isthen reacted with a substituted benzylbromide in the presence of LiHMDSin THF at cold temperature to give the Intermediate of Formula 12. TheIntermediate Formula 12 is then converted to the hydroxamic acidcompound of the invention of Formula 4 by treatment with potassiumcyanide (KCN) and hydroxylamine (NH₂OH—H₂O) in the presence of asuitable solvent or solvent mixture, such as tetrahydrofuran (THF) andmethanol (MeOH). The compounds of Formula 4 represent a subgenus of thecompounds of Formula 1.

General Scheme 5 discloses a synthetic route to yet another particularclass of compounds of the invention which are shown in Table 2 andwherein the R² group with reference to Formula 1 is alkylphenyl. In thisreaction scheme the starting material is an omega bromo alkanoic acidwhere the variable n has the same definition as in connection withFormula 1. The omega bromo alkanoic acid is reacted withtriphenylphosphine (PPh₃) in a suitable solvent, such as toluene, toprovide the Intermediate Formula 13. The Intermediate Formula 13 is thenreacted in a Wittig reaction with a substituted benzaldehyde to providethe Intermediate Formula 14. The variables R¹ and m in the formula ofthe substituted benzaldehyde are defined as in connection withFormula 1. The olefinic double bond of the Intermediate Formula 14 isreduced by catalytic hydrogenation to the carboxylic acid compoundIntermediate Formula 15. The Intermediate Formula 15 is reacted with(R)-4-benzyloxazolidin-2-one in the presence of triethylamine, pivaloylchloride and LiCl in an aprotic solvent, such as THF, to give theIntermediate Formula 16. Reaction of the Intermediate Formula 16 with asubstituted bemzylbromide in the presence of LiHMDS in THF yields theIntermediate Formula 17. The Intermediate Formula 17 is then convertedto the hydroxamic acid compound of the invention of Formula 5 bytreatment with potassium cyanide (KCN) and hydroxylamine (NH₂OH—H₂O) inthe presence of a suitable solvent or solvent mixture, such astetrahydrofuran (THF) and methanol (MeOH). The compounds of Formula 5are within the scope of the invention and represent a subgenus of thecompounds of Formula 1.

Preferred Examples

Referring now to the variable R¹ in Formula 1, in the compounds of theinvention R¹ represents a substituent on the phenyl group shown in theformula. In the preferred compounds of the invention R¹ is F, Cl,methyl, methoxy or phenyl. The variable m is preferably the integerselected from 1, 2 and 3. Even more preferably the variable m is 2 or 3.Particularly preferred are compounds of the invention where m is 2, andthe R¹ are methyl and fluoro, with the methyl group being in the 3(meta) position and the fluoro being in the 4 (para) position. Alsoparticularly preferred are compounds where m is 3, and there is a methylgroup in the 3,5 (meta, meta) positions and a fluoro in the 4 (para)position of the phenyl ring.

Referring now to the variable R² in Formula 1 in the preferred compoundsof the invention R² is CN, alkyl of 1 to 8 carbons, alkylphenyl wherethe alkyl group has 1 to 6 carbons, (CH₂)_(n)OCH₂-phenyl, (CH₂)_(n)CF₃where n is 1 to 6, CH₂OR³ where R₃ is H or t-butyl. In some preferredcompounds R² is H. Compounds are also preferred where R² is an alkenylgroup having 2 to 8 carbon atoms and one double bond, where R² is(CH₂)_(n)NHR⁴ where the R group is alkylphenyl or alkylheteroaryl,alkylheteroaryl condensed with a benzene ring, where the phenyl orheteroaryl can be substituted with 0 to 3 R¹ groups, or R⁴ isalkylcyclohexyl Compounds are also preferred where R² is (CH₂)_(n)NR⁶R⁴and R⁶ is alkyl.

EXPERIMENTAL

Scheme and experimental descriptions for the synthesis of the specificexemplary compounds are given below. The LC/MS data given was obtainedusing the following conditions: LC/MSD/ELSD analysis performed in ESIpositive mode with an Agilent 1100 LC/MSD VL system equipped withAgilent 1100 HP PDA and Sedex 75 ELSD detectors. Column: Zorbax EclipseSD-C18, 5 μm, 4.6×75 mm; Temperature set at 25° C.; Mobile Phase: %A=0.025% trifluoroacetic acid-water, % B=0.025% trifluoroaceticacid-acetonitrile; or: % A=0.10% formic acid-water, % B=0.10 formicacid-acetonitrile Linear Gradient: 20%-98% B in 15 min.; Flow rate: 1.0mL/min.; ELSD gain set @ 3; UV set at 254 nm and 214 nm.

Reagents and conditions: (a) 0.5 eq of 4-fluoro-3-methylbenzaldehyde, 1eq of piperidine, pyridine, 100° C.; (b) 20% (w/w) of Pd/C, MeOH, H₂,rt; (c) 3 eq of O-(tetrahydro-pyran-2-yl)-hydroxylamine, 1 eq of HOBT, 5eq of NMM, 1.5 eq of EDC, DCM, rt; (d) TFA/DCM (1:1), rt.

2-(4-Fluoro-3-methyl-benzylidene)-hexanoic acid (A)

A mixture of 2-butyl-malonic acid (2.319 g, 14.482 mmol),4-fluoro-3-methylbenzaldehyde (1.000 g, 7.241 mmol), and piperidine(1.232 g, 14.482 mmol) in 10 mL of pyridine was heated to 100° C. andstirred at this temperature for 16 h. After cooling to room temperature,the reaction mixture was poured into 25 mL of concentrated HClcontaining 50 g of ice, and then extracted with ethyl acetate. Theorganic extracts were combined and dried over anhydrous Na₂SO₄,concentrated under reduced pressure, the product isolated by Flashchromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes togive the title compound as yellow liquid (1.370 g, 80% yield). LC-MS:t_(R)=9.5 min; m/z 237 (M+H)⁺.

2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (B)

To a solution of 2-(4-Fluoro-3-methyl-benzylidene)-hexanoic acid (0.850g, 3.600 mmol) in 20 mL of MeOH, was added Pd—C (10 wt % on activatedcarbon, 0.170 g). After stirring at room temperature under H₂ for 16 h,the reaction mixture was filtered through a pad of Celite and washedwith MeOH. The filtrate was concentrated under reduced pressure and thecrude product was used directly in the next step without furtherpurification. LC-MS: t_(R)=9.3 min; m/z 239 (M+H)⁺.

2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid(tetrahydro-pyran-2-yloxy)-amide (C)

To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (0.498 g,2.091 mmol), O-(tetrahydro-pyran-2-yl)-hydroxylamine (0.735 g, 6.274mmol), HOBT (0.282 g, 2.091 mmol), and N-methyl morphine (1.058 g,10.455 mmol) in 20 mL of dichloromethane, was added EDCI (0.601 g, 3.137mmol). After stirring at room temperature under N₂ for 64 h, thereaction mixture was diluted with 60 mL of water and extracted withdichloromethane (60 mL×3). The organic extracts were combined and driedover anhydrous Na₂SO₄. After removing the solvents under reducedpressure, the product was isolated by Flash chromatography (silica gel)eluting with 0-40% ethyl acetate/hexanes to give the title compound as apale yellow solid (0.423 g, 60% yield). LC-MS: t_(R)=9.1 min; m/z 338(M+H)⁺.

2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid hydroxyamide (Compound167266)

To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid(tetrahydro-pyran-2-yloxy)-amide (0.0.358 g, 1.062 mmol) in 5 mL ofdichloromethane, was added trifluoroacetic acid (5 mL). After stirringat room temperature for 3 h, the reaction mixture was concentrated underreduced pressure. The product was isolated by Flash chromatography(silica gel) eluting with 0-10% methanol/dichoromethane to give thetitle compound as an off-white solid (0.059 g, 22% yield). LC-MS:t_(R)=7.1 min; m/z 254 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 0.89 (t, J=6.60Hz, 3H), 1.27-1.36 (m, 4H), 1.39-1.49 (m, 1H), 1.60-1.67 (m, 1H), 2.23(d, J=1.50 Hz, 3H), 2.24-2.32 (m, 1H), 2.62 (dd, J=13.50, 5.40 Hz, 1H),2.79 (dd, J=13.50, 9.60 Hz, 1H), 6.88 (t, J=9.60 Hz, 1H), 6.95-6.96 (m,1H), 7.01 (t, J=7.50 Hz, 1H).

Reagents and conditions: (a) 1 eq of 3,5-dimethyl-4-fluorobenzaldehyde,THF, microwave heating to 100° C.; (b) 20% (w/w) of Pd/C, MeOH, H₂, rt;(c) KCN (5 mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

Ethyl 3-(4-fluoro-3,5-dimethylphenyl)-2-methylacrylate (A2)

Ethoxy-carbonylethylene triphenyl phosphorane (0.476 g, 1.314 mmol) and3,5-dimethyl-4-fluorobenzaldehyde (0.200 g, 1.314 mmol) were weighedinto a microwave tube followed by the addition of 3 mL of THF. Afterstirred under microwave irradiation at 100° C. for 1 h, the reactionmixture was concentrated under reduced pressure. The product wasisolated by Flash column chromatography (silica gel column) eluting with0-30% ethyl acetate/hexanes to give the title compound as a white solid(0.267 g, 86% yield). LC-MS: t_(R)=10.6 & 11.3 min; m/z 237 (M+H)⁺.

ethyl 2-(4-fluoro-3,5-dimethylbenzyl)propanoate (B2)

To a solution of Ethyl 3-(4-fluoro-3,5-dimethylphenyl)-2-methylacrylate(0.190 g, 0.855 mmol) in 10 mL of MeOH, was added Pd (10 wt % onactivated carbon, 0.038 g). After stirring at room temperature under H₂(1 atm) for 40 h, the reaction mixture was filtered through a pad ofCelite and washed with MeOH. The filtrate was concentrated under reducedpressure. The crude product was used directly in the next step withoutfurther purification (0.138 g, 88% yield). LC-MS: t_(R)=10.9 min; m/z239 (M+H)⁺.

2-(4-fluoro-3,5-dimethylbenzyl)-N-hydroxypropanamide (Compound 167858)

To a solution of ethyl 2-(4-fluoro-3,5-dimethylbenzyl)propanoate (0.135g, 0.567 mmol) in 5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1), was added KCN(0.002 g, 0.028 mmol). After stirring at room temperature for 63 h, thereaction mixture was concentrated under reduced pressure. The productwas isolated by Flash column chromatography (silica gel column) elutingwith 0-10% methanol/dichloromethane to give the title compound as anoff-white solid (0.045 g, 35% yield). LC-MS: t_(R)=5.8 min; m/z 226(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 1.11 (d, J=6.88 Hz, 3H), 2.18 (d,J=1.68 Hz, 6H), 2.37-2.41 (m, 1H), 2.53 (dd, J=13.43, 6.38 Hz, 1H), 2.78(dd, J=13.42, 8.89 Hz, 1H), 6.82 (d, J=7.05 Hz, 2H); ¹³C NMR (125.75MHz, CD₃OD) δ 14.53 (d, J=4.15 Hz), 18.05, 40.04, 41.31, 125.02 (d,J=17.86 Hz), 130.44 (d, J=4.53 Hz), 135.91 (d, J=3.65 Hz), 160.83,175.31

Reagents and conditions: (a) 1 eq of (R)-4-benzyloxazolidin-2-one, 1 eqof n-BuLi (2.5 M in hexane), THF, −78° C. to rt; (b) 1.5 eq of LiHMDS(1.0 M in THF), 1.1 eq of 3,5-dimethyl-4-fluorobenzyl bromide, THF, −78°C. to rt; (c) O₃, 5 eq of Me₂S, DCM, −78° C. to rt; (d) 1.2 eq of4-fluorobenzylamine, 1.4 eq of NaBH(OAc)₃, dichloroethane, rt; (e) KCN(5 mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

(R)-3-((E)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one (A3)

To a cooled (−78° C.) solution of (R)-4-benzyloxazolidin-2-one (2.817 g,15.899 mmol) in 40 mL of THF, was added n-BuLi (6.4 mL, 15.899 mmol, 2.5M in hexane). The resulting mixture was stirred at −78° C. under N₂ for15 min. and then (E)-8-methylnon-6-enoyl chloride (3.000 g, 15.899 mmol)was added. After stirring at −78° C. for 1 h and then being warmed toroom temperature under N₂ for overnight, the reaction mixture wasquenched with 80 mL of NH₄Cl solution and extracted with dichloromethane(60 mL×3). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The product was isolated byFlash column chromatography (silica gel column) eluting with 0-30% ethylacetate/hexanes to give the title compound as colorless oil (4.468 g,85% yield). GC-MS: t_(R)=6.2 min; m/z 329 (M⁺).

(R)-3-((S,E)-2-(4-fluoro-3,5-dimethylbenzyl)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one(B3)

To a cooled (−78° C.) solution of(R)-3-((E)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one (2.000 g, 6.071mmol) in 40 mL of THF, was added LiHMDS (9.1 mL, 9.1 mmol, 1.0 M inTHF). The resulting mixture was stirred at −78° C. under N₂ for 1 h andthen a solution of 3,5-dimethyl-4-fluorobenzyl bromide (1.450 g, 6.678mmol) in 10 mL of THF was added. After being stirred at −78° C. for 1 hthe reaction mixture was warmed to room temperature for 2 h, and thenquenched with 80 mL of NH₄Cl solution and extracted with dichloromethane(60 mL×3). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The product was isolated byFlash column chromatography (silica gel column) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(1.925 g, 68% yield). GC-MS: t_(R)=8.8 min; m/z 465 (M⁺).

(S)-5-(4-fluoro-3,5-dimethylbenzyl)-6-((R)-4-benzyl-2-oxooxazolidin-3-yl)-6-oxohexanal(C3)

A solution of(R)-3-((S,E)-2-(4-fluoro-3,5-dimethylbenzyl)-8-methylnon-6-enoyl)-4-benzyloxazolidin-2-one(0.541 g, 1.162 mmol) in 10 mL of dichloromethane was cooled to −78° C.A stream of O₃ was bubbled through the solution until it became blue.The solution was sparged with O₂ was until the blue color disappeared.Me₂S (0.43 mL, 5.810 mmol) was added and the solution warmed to roomtemperature and stirred for overnight. The reaction mixture wasconcentrated under reduced pressure and the product isolated by Flashcolumn chromatography (silica gel column) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(0.412 g, 83% yield). GC-MS: t_(R)=8.5 min; m/z 425 (M⁺).

(R)-3-((S)-2-[4-fluoro-3,5-dimethylbenzyl)-6-(4-fluorobenzylamino)-hexanoyl]-4-benzyloxazolidin-2-one(D3)

To a solution of(S)-5-(4-fluoro-3,5-dimethylbenzyl)-6-((R)-4-benzyl-2-oxooxazolidin-3-yl)-6-oxohexanal(0.039 g, 0.0917 mmol) and 4-fluorobenzyl amine (0.014 g, 0.110 mmol) in3 mL of dichloroethane, was added NaBH(OAc)₃ (0.027 g, 0.128 mmol).After stirring at room temperature for overnight, the reaction wasquenched with 20 mL of saturated NaHCO₃ solution and the reactionmixture was extracted with ethyl acetate (20 mL×3). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The product was isolated by Flash column chromatography(silica gel column) eluting with 0-10% methanol/dichloromethane to givethe title compound as light yellow oil (0.030 g, 62% yield). LC-MS:t_(R)=6.9 min; m/z 535 (M+H)⁺.

(S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluorobenzylamino)-N-hydroxyhexanamide(Compound 168117)

To a solution of(R)-3-((S)-2-[4-fluoro-3,5-dimethylbenzyl)-6-(4-fluorobenzylamino)-hexanoyl]-4-benzyloxazolidin-2-one(0.030 g, 0.0561 mmol) in 2.5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1), wasadded KCN (0.001 g, 0.015 mmol). After stirring at room temperature forovernight, the reaction mixture was acidified with concentrated HCl topH=2 and filtered. The product was isolated by RP-HPLC eluting with20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the titlecompound as an off-white solid (0.005 g, 23% yield). LC-MS: t_(R)=4.8min, m/z 391 (M+H)⁺, ¹H NMR (300 MHz, CD₃OD) δ 1.27-1.38 (m, 2H),1.40-1.57 (m, 2H), 1.58-1.75 (m, 2H), 2.19 (s, 6H), 2.20-2.31 (m, 1H),2.52-2.66 (m, 1H), 2.70-2.82 (m, 1H), 3.00 (t, J=7.91 Hz, 2H), 4.17 (s,2H), 6.82 (d, J=6.74 Hz, 2H), 7.20 (t, J=8.64 Hz, 2H), 7.51 (dd, J=8.20,5.27 Hz, 2H).

Reagents and conditions: (a) 3 eq of 4-fluoro-3-methylbenzyl bromide, 5eq of KOH, toluene, reflux; (b) 0.98 eq of pivaloyl chloride, 2.6 eq ofEt₃N, 0.98 eq of LiCl, 0.95 eq of (R)-4-benzyloxazolidin-2-one, THF,−10° C. to rt; (c) 1.5 eq of LiHMDS (1.0 M in THF), 3 eq of3,5-dimethyl-4-fluorobenzyl bromide, THF, −78° C. to rt; (d) KCN (5 mol%), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

6-(4-fluoro-3-methylbenzyloxy)hexanoic acid (A4)

To a solution of oxepan-2-one (0.562 g, 4.925 mmol) and4-fluoro-3-methylbenzyl bromide (3.000 g, 14.774 mmol) in 20 mL oftoluene, was added KOH (1.382 g, 24.625 mmol). The mixture was refluxedfor 86 h and after cooling to room temperature, the reaction mixture wasdiluted with water (80 mL) and washed with ether. The aqueous layer wasacidified with concentrated HCl to pH=2 and extracted with ether (50mL×3). The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure to give the title compound ascolorless oil which was used directly in the next step without furtherpurification (1.173 g, 94% yield). LC-MS: t_(R)=8.0 min, m/z 277 (M+H)⁺.

(R)-3-(6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one(B4)

To a cooled (−10° C.) solution of 6-(4-fluoro-3-methylbenzyloxy)hexanoicacid (0.565 g, 2.222 mmol) in 15 mL of THF, were added stepwisetriethylamine (0.80 mL, 5.713 mmol) and pivaloyl chloride (0.27 mL,2.179 mmol). The reaction mixture was stirred at −10° C. for 1 h andthen LiCl (0.092 g, 2.179 mmol) and (R)-4-benzyloxazolidin-2-one (0.375g, 2.116 mmol) were added stepwise. After warmed slowly to roomtemperature with stirring overnight, the reaction mixture was dilutedwith ethyl acetate (80 mL) and washed with saturated NaHCO₃ solution andbrine. The organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The product was isolated by Flash columnchromatography (silica gel column) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(0.482 g, 52% yield). LC-MS: t_(R)=11.2 min; m/z 414 (M+H)⁺.

(R)-3-((S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one(C4)

To a cooled (−78° C.) solution of(R)-3-(6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one(0.220 g, 0.532 mmol) in 5 mL of THF, was added LiHMDS (0.80 mL, 0.80mmol, 1.0 M in THF). The resulting mixture was stirred at −78° C. underN₂ for 1 h and then a solution of 3,5-dimethyl-4-fluorobenzyl bromide(0.346 g, 1.596 mmol) in 3 mL of THF was added. After stirring at −78°C. for 1 h the reaction mixture was warmed to room temperature for 2 h,and then quenched with 20 mL of NH₄Cl solution and extracted withdichloromethane (20 mL×3). The combined organic extracts were dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The productwas isolated by Flash column chromatography (silica gel column) elutingwith 0-100% dichloromethane/hexanes to give the title compound ascolorless oil (0.106 g, 36% yield). GC-MS: t_(R)=15.6 min; m/z 549 (M⁺).

(S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluoro-3-methylbenzyloxy)-N-hydroxyhexanamide(Compound 168141)

To a solution of(R)-3-((S)-2-(4-fluoro-3,5-dimethylbenzyl)-6-(4-fluoro-3-methylbenzyloxy)hexanoyl)-4-benzyloxazolidin-2-one(0.040 g, 0.0728 mmol) in 2.5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1), KCN(0.001 g, 0.015 mmol) was added. After stirring at room temperature forovernight, the reaction mixture was acidified with concentrated HCl topH=2 and filtered. The filtrate was purified by RP-HPLC eluting with20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the titlecompound as an off-white solid (0.005 g, 23% yield). LC-MS: t_(R)=9.6min, m/z 406 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 1.28-1.51 (m, 4H),1.52-1.70 (m, 2H), 2.18 (s, 6H), 2.25 (s, 3H), 2.26-2.33 (m, 1H),2.52-2.63 (m, 1H), 2.68-2.79 (m, 1H), 3.44 (t, J=6.30 Hz, 2H), 4.40 (s,2H), 6.81 (d, J=7.03 Hz, 2H), 6.97 (t, J=9.08 Hz, 1H), 7.09-7.15 (m,1H), 7.18 (d, J=7.32 Hz, 1H).

Reagents and conditions: (a) 1.1 eq of PPh₃, toluene, reflux; (b) 0.6 eqof 4-fluoro-3-methylbenzaldehyde, 3 eq of t-BuOK (1M in THF), benzene,reflux; (c) H₂, 20% (w/w) of Pd/C, MeOH; (d) 1.1 eq of pivaloylchloride, 2.7 eq of Et₃N, 1.1 eq of LiCl, 1.1 eq of(R)-4-benzyloxazolidin-2-one, THF, −10° C. to rt; (e) 1.5 eq of LiHMDS(1.0 M in THF), 3 eq of 3,5-dimethyl-4-fluorobenzyl bromide, THF, −78°C. to rt; (f) KCN (5 mol %), THF/MeOH/50% NH₂OH—H₂O (2:2:1), rt.

7-Carboxyheptanyltriphenylphosphonium bromide (A5)

A solution of 7-bromoheptanoic acid (5.000 g, 23.913 mmol) and PPh₃(6.899 g, 26.304 mmol) in 50 mL of toluene was refluxed for 63 h. Aftercooling to room temperature, the solvent was removed under reducedpressure and the residue was tritited with ether three times and driedin vacuum to give the title compound as a white foam solid (9.240 g, 82%yield).

8-(4-fluoro-3-methylphenyl)oct-7-enoic acid (B5)

To a suspension of 7-Carboxyheptanyltriphenylphosphonium bromide (9.240g, 19.602 mmol) in 100 mL of benzene, was added t-BuOK (58.8 mL, 58.8mmol, 1M in THF). The resulting mixture was refluxed for 1 h and then4-fluoro-3-methylbenzaldehyde (1.43 mL, 11.761 mmol) was added via asyringe. The mixture was continued to reflux under N₂ for 63 h. Aftercooling to room temperature, the reaction mixture was washed with water(80 mL). The aqueous layer was acidified with concentrated HCl to pH=2and extracted with ethyl acetate (30 mL×3). The combined organicextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The product was isolated by Flash column chromatography(silica gel column) eluting with 0-30% ethyl acetate/hexanes to give thetitle compound as colorless oil (3.150 g, >99% yield). LC-MS: t_(R)=9.6min, m/z 251 (M+H)⁺.

8-(4-fluoro-3-methylphenyl)octanoic acid (C5)

To a solution of 8-(4-fluoro-3-methylphenyl)oct-7-enoic acid (0.976 g,3.899 mmol) in 30 mL of MeOH, was added 10% Pd on C (0.195 g). Afterstirring at room temperature under H₂ for 63 h, the reaction mixture wasfiltered through a pad of Celite and washed with ethyl acetate. Thefiltrate was concentrated under reduced pressure. The residue was useddirectly in the next step without further purification (0.938 g, 95%yield). LC-MS: t_(R)=10.1 min, m/z 253 (M+H)⁺.

(R)-3-(8-(4-fluoro-3-methylphenyl)octanoyl)-4-benzyloxazolidin-2-one(D5)

To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoicacid (0.452 g, 1.791 mmol) in 15 mL of THF, were added stepwisetriethylamine (0.67 mL, 4.836 mmol) and pivaloyl chloride (0.24 mL,1.971 mmol). The reaction mixture was stirred at −10° C. for 1 h andthen LiCl (0.084 g, 1.971 mmol) and (R)-4-benzyloxazolidin-2-one (0.349g, 1.971 mmol) were added stepwise. After warming slowly to roomtemperature and stirring overnight, the reaction mixture was dilutedwith ethyl acetate (80 mL) and washed with saturated NaHCO₃ solution andbrine. The organic layer was dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The product was isolated by Flash columnchromatography (silica gel column) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(0.666 g, 90% yield). GC-MS: t_(R)=9.6 min; m/z 411 (M⁺).

(S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoicacid hydroxyamide (Compound 168124)

To a solution of(R)-4-Benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoyl]-oxazolidin-2-one(0.036 g, 0.0657 mmol) in 2.5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1), wasadded KCN (0.001 g, 0.007 mmol). After stirring at room temperature forovernight, the reaction mixture was acidified with concentrated HCl topH=2 and filtered. The product was isolated by RP-HPLC eluting with20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the titlecompound as an off-white solid (0.005 g, 18% yield). LC-MS: t_(R)=11.1min, m/z 404 (M+H)⁺; ¹H NMR (300 MHz, CD₃OD) δ 1.21-1.33 (m, 6H),1.34-1.48 (m, 2H), 1.49-1.66 (m, 2H), 2.18 (s, 6H), 2.21 (s, 3H),2.23-2.32 (m, 1H), 2.51 (t, J=7.32 Hz, 2H), 2.56-2.62 (m, 1H), 2.67-2.78(m, 1H), 6.81 (d, J=6.74 Hz, 2H), 6.88 (t, J=9.37 Hz, 1H), 6.91-6.97 (m,1H), 7.00 (d, J=7.03 Hz, 1H).

Reagents and conditions: (a) 1.5 eq of Boc₂O, saturated NaHCO₃ solution,dioxane, rt; (b) 1.5 eq of NaH (60% in mineral oil), 2 eq of MeI, THF,rt; (c) TFA/DCM (1:1), rt.

[3-(4-Fluoro-phenyl)-propyl]-carbamic acid tert-butyl ester (A6)

To a solution of 3-(4-fluoro-phenyl)-propylamine (0.300 g, 1.958 mmol)and di-tert-butyl dicarbonate (0.641 g, 2.938 mmol) in 8 mL of dioxane,was added 5 mL of saturated aqueous NaHCO₃ solution. After stirring atroom temperature for 64 h, the reaction mixture was diluted with 50 mLof water and extracted with dichloromethane (50 mL×3). The combinedorganic extracts were dried, filtered. Removal of the solvent underreduced pressure provided the title compound as a white solid (0.525g, >99% yield), which was used directly in the next step without furtherpurification. GC-MS: t_(R)=8.9 min; m/z 253 (M⁺).

[3-(4-Fluoro-phenyl)-propyl]-methyl-carbamic acid tert-butyl ester (B6)

To a mixture of [3-(4-fluoro-phenyl)-propyl]-carbamic acid tert-butylester (0.390 g, 1.540 mmol) and NaH (0.092 g, 2.310 mmol, 60% in mineraloil) in 10 mL of THF, was added via a syringe MeI (0.19 mL, 3.080 mmol).After stirring overnight at room temperature under N₂, the reaction wasquenched with NH₄Cl solution (40 mL) and the resulting mixture extractedwith dichloromethane (40 mL×3). The combined organic extracts weredried, filtered, and concentrated under reduced pressure. The productwas isolated using Flash column chromatography (silica gel) eluting with0-30% ethyl acetate/hexanes to give the title compound as colorless oil(0.417 g, >99% yield). GC-MS: t_(R)=8.6 min; m/z 267 (M⁺).

[3-(4-Fluoro-phenyl)-propyl]-methyl-amine (C6)

To a solution of [3-(4-fluoro-phenyl)-propyl]-methyl-carbamic acidtert-butyl ester (0.417 g, 1.560 mmol) in 3 mL of dichloromethane, wasadded trifluoroacetic acid (3 mL). After stirring at room temperaturefor 3 h, the reaction mixture was concentrated under reduced pressure.The residue was re-dissolved in 20 mL of ethyl acetate and the resultingsolution was washed with NaOH solution (1N) and brine, and dried overanhydrous Na₂SO₄. Removal of the solvent under reduced pressure providedthe title compound as a colorless oil (0.189 g, 72% yield), which wasused directly in the next step (Step d of Specific Scheme 7) withoutfurther purification. GC-MS: t_(R)=5.6 min; m/z 167 (M⁺).

Reagents and conditions: (a) 1 eq of (R)-4-benzyloxazolidin-2-one, 1.1eq of n-BuLi (2.5 M in hexane), THF, −78° C. to rt; (b) 1.5 eq of LiHMDS(1.0 M in THF), 1.1 eq of 3,5-dimethyl-4-fluorobenzyl bromide, THF, −78°C. to rt; (c) O₃, 5 eq of Me₂S, DCM, −78° C. to rt; (d) 1.2 eq of[3-(4-fluoro-phenyl)-propyl]-methyl-amine (C6), 1.4 eq of NaBH(OAc)₃, 2eq of HOAc, dichloroethane, rt; (e) KCN (5 mol %), THF/MeOH/50%NH₂OH—H₂O (2:2:1), rt.

(R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (A7)

To a cooled (−78° C.) solution of (R)-4-benzyloxazolidin-2-one (2.242 g,12.652 mmol) in 30 mL of THF, was added n-BuLi (5.6 mL, 13.917 mmol, 2.5M in hexane). The resulting mixture was stirred at −78° C. under N₂ for15 min and then pent-4-enoyl chloride (1.500 g, 12.652 mmol) was added.After stirring at −78° C. for 1 h the reaction was warmed to roomtemperature under N₂ and stirred overnight. The reaction mixture wasquenched with 60 mL of aqueous NH₄Cl solution and extracted withdichloromethane (50 mL×3). The combined organic extracts were dried,filtered, and concentrated under reduced pressure. The product wasisolated by Flash column chromatography (silica gel) eluting with 0-30%ethyl acetate/hexanes to give the title compound as colorless oil (2.146g, 65% yield). GC-MS: t_(R)=4.2 min; m/z 259 (M⁺).

(R)-4-Benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one(B7)

To a cooled (−78° C.) solution of(R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (0.500 g, 1.928 mmol) in 15mL of THF, was added LiHMDS (2.9 mL, 2.9 mmol, 1.0 M in THF). Theresulting mixture was stirred at −78° C. under N₂ for 1 h and then asolution of 3,5-dimethyl-4-fluorobenzyl bromide (0.460 g, 2.121 mmol) in5 mL of THF was added. After being stirred at −78° C. for 1 h followedby warming to room temperature over 2 h, the reaction mixture wasquenched with 50 mL of aqueous NH₄Cl solution and extracted withdichloromethane (50 mL×3). The combined organic extracts were dried,filtered, and concentrated under reduced pressure. The product wasisolated by Flash column chromatography (silica gel) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(0.221 g, 56% yield). GC-MS: t_(R)=7.0 min; m/z 395 (M⁺).

4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-((S)-4-fluoro-3,5-dimethyl-benzyl)-4-oxo-butyraldehyde(C7)

A solution of(R)-4-benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one(0.220 g, 0.556 mmol) in 10 mL of dichloromethane was cooled to −78° C.and O₃ was bubbled through the solution until the color became blue.Then O₂ was bubbled through the solution until the blue colordisappeared. Me₂S (0.20 mL, 2.723 mmol) was added and after warming toroom temperature and stirring overnight, the reaction mixture wasconcentrated under reduced pressure. The product was isolated by Flashcolumn chromatography (silica gel) eluting with 0-100%dichloromethane/hexanes to give the title compound as colorless oil(0.157 g, 71% yield). GC-MS: t_(R)=7.7 min; m/z 397 (M⁺).

(R)-4-Benzyl-3-((S)-2-(4-fluoro-3,5-dimethyl-benzyl)-4-{[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-butyryl)-oxazolidin-2-one(D7)

To a solution of(R)-4-benzyl-3-[(S)-2-(4-fluoro-3,5-dimethyl-benzyl)-pent-4-enoyl]-oxazolidin-2-one(0.045 g, 0.113 mmol), [3-(4-fluoro-phenyl)-propyl]-methyl-amine (C6,0.023 g, 0.136 mmol), and acetic acid (0.014 g, 0.226 mmol) in 3 mL ofdichloroethane, was added NaBH(OAc)₃ (0.034 g, 0.158 mmol). Afterstirring at room temperature overnight, the reaction was quenched with20 mL of saturated aqueous NaHCO₃ solution and the reaction mixtureextracted with ethyl acetate (20 mL×3). The combined organic extractswere dried, filtered, and concentrated under reduced pressure. Theproduct was isolated by Flash column chromatography (silica gel) elutingwith 0-10% methanol/dichloromethane to give the title compound ascolorless oil (0.046 g, 75% yield). LC-MS: t_(R)=7.7 min; m/z 549(M+H)⁺.

(S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-4-{[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-N-hydroxy-butyramide(Compound 168172

To a solution of(R)-4-benzyl-3-((S)-2-(4-fluoro-3,5-dimethyl-benzyl)-4-{[3-(4-fluoro-phenyl)-propyl]-methyl-amino}-butyryl)-oxazolidin-2-one(0.033 g, 0.0601 mmol) in 2.5 mL of THF/MeOH/50% NH₂OH—H₂O (2:2:1), wasadded KCN (0.001 g, 0.006 mmol). After stirring at room temperatureovernight, the reaction mixture was acidified with concentrated HCl topH=2 and filtered. The product was isolated by RP-HPLC eluting with20-100% acetonitrile (0.025% TFA)/water (0.025% TFA) to give the titlecompound as an off-white solid (0.016 g, 66% yield). LC-MS: t_(R)=5.5min, m/z 405 (M+H)⁺.

Abbreviations:

DMF=dimethylformamideHOBt=1-hydroxybenzotriazole

NMM=N-methylmorpholine

EDC=N-(-dimethylaminopropyl)-N′-ethylcarbodiimideDCM=dichloromethaneTFA=trifluoroacetic acidMS molecular sievesLiHMDS=Lithium bis(trimethylsilyl)amideAdditional Examples from Table 1

-   2-Benzyl-hexanoic acid hydroxyamide (Compound 167550) Prepared    according to General Scheme 1.

LC-MS: t_(R)=6.3 min, m/z 222 (M+H)⁺.

-   2-(4-Fluoro-3,5-dimethyl-benzyl)-hexanoic acid hydroxyamide    (Compound 167533) Prepared according to General Scheme 1.

LC-MS: t_(R)=7.8 min, m/z 268 (M+H)⁺.

Additional Examples in Table 2

-   3-(4-Fluoro-3,5-dimethyl-phenyl)-N-hydroxy-propionamide    (Compound 167857) Prepared according to General Scheme 2.

LC-MS: t_(R)=5.4 min, m/z 212 (M+H)⁺.

-   3-(4-Fluoro-3,5-dimethyl-phenyl)-N-hydroxy-2-methyl-propionamide    (Compound 167858) Prepared according to General Scheme 2.

LC-MS: t_(R)=5.8 min, m/z 226 (M+H)⁺.

-   2-Cyano-3-(4-fluoro-3,5-dimethyl-phenyl)-N-hydroxy-propionamide    (Compound 167914)) Prepared according to General Scheme 2.

LC-MS: t_(R)=5.4 min, m/z 237 (M+H)⁺.

-   2-(4-Bromo-phenyl)-3-(4-fluoro-3,5-dimethyl-phenyl)-N-hydroxy-propionamide    (Compound 167856) Prepared according to General Scheme 3.

LC-MS: t_(R)=8.5 min, m/z 367 (M+H)⁺.

-   (R)-2-(4-Bromo-phenyl)-3-(4-fluoro-3,5-dimethyl-phenyl)-N-hydroxy-propionamide    (Compound 168009) Prepared according to General Scheme 3.

LC-MS: t_(R)=8.4 min, m/z 367 (M+H)⁺.

-   (S)-2-(4-Bromo-phenyl)-3-(4-fluoro-3,5-dimethyl-phenyl)-N-hydroxy-propionamide    (Compound 167973) Prepared according to General Scheme 3.

LC-MS: t_(R)=8.4 min, m/z 366/368 (M+H)⁺.

-   (R)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-methyl-non-6-enoic acid    hydroxyamide (Compound 168051) Prepared according to General Scheme    3

LC-MS: t_(R)=9.8 min, m/z 322 (M+H)⁺.

-   (R)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-methyl-nonanoic acid    hydroxyamide (Compound 168052) Prepared according to General Scheme    3.

LC-MS: t_(R)=10.4 min, m/z 324 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-methyl-non-6-enoic acid    hydroxyamide (Compound 168023) Prepared according to General Scheme    3.

LC-MS: t_(R)=9.7 min, m/z 322 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-methyl-nonanoic acid    hydroxyamide (Compound 168031) Prepared according to General Scheme    3.

LC-MS: t_(R)=10.4 min, m/z 324 (M+H)⁺.

Additional Examples in Table 3

-   (S)-6-(2-Ethyl-butylamino)-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168171) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.3 min, m/z 367 (M+H)⁺.

-   (S)-6-(Cyclohexylmethyl-amino)-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168170) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.2 min, m/z 379 (M+H)⁺.

-   (S)-6-Benzylamino-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic acid    hydroxyamide (Compound 168149) Prepared according to General Scheme    3.

LC-MS: t_(R)=4.9 min, m/z 373 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-(4-fluoro-phenylamino)-hexanoic    acid hydroxyamide (Compound 168132) Prepared according to General    Scheme 3.

LC-MS: t_(R)=8.5 min, m/z 362 (M+H)⁺.

-   (S)-2-(4-Fluoro-3-methyl-benzyl)-6-(4-fluoro-3-methyl-benzylamino)-hexanoic    acid hydroxyamide (Compound 168139) Prepared according to General    Scheme 3.

LC-MS: t_(R)=4.8 min, m/z 391 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-(4-fluoro-3-methyl-benzylamino)-hexanoic    acid hydroxyamide (Compound 168050) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.1 min, m/z 405 (M+H)⁺.

-   (S)-6-(4-Fluoro-benzylamino)-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168117). Prepared according to General    Scheme 3.

LC-MS: t_(R)=4.8 min, m/z 391 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-[2-(4-fluoro-phenyl)-ethylamino]-hexanoic    acid hydroxyamide (Compound 168122) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.3 min, m/z 405 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-[3-(4-fluoro-phenyl)-propylamino]-hexanoic    acid hydroxyamide (Compound 168123) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.5 min, m/z 419 (M+H)⁺.

-   (S)-6-(4-Chloro-benzylamino)-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168125) Prepared according to General    Scheme 3.

LC-MS: t_(R)=6.0 min, m/z 407/409 (M+H)⁺.

-   (S)-6-[(Biphenyl-3-ylmethyl)-amino]-2-(4-fluoro-3-methyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168140) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.7 min, m/z 435 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-(4-fluoro-3-methyl-benzyloxy)-hexanoic    acid hydroxyamide (Compound 168141) Prepared according to General    Scheme 4.

LC-MS: t_(R)=9.6 min, m/z 406 (M+H)⁺.

-   (S)-6-[(4-Fluoro-benzyl)-methyl-amino]-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168126) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.7 min, m/z 405 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoic    acid hydroxyamide (Compound 168124) Prepared according to General    Scheme 5.

LC-MS: t_(R)=11.1 min, m/z 404 (M+H)⁺.

-   (S)-6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168148) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.0 min, m/z 417 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-[(5-methyl-furan-2-ylmethyl)-amino]-hexanoic    acid hydroxyamide (Compound 168157) Prepared according to General    Scheme 3.

LC-MS: t_(R)=4.9 min, m/z 377 (M+H)⁺.

-   (S)-2-(4-Fluoro-3,5-dimethyl-benzyl)-6-[(pyrazin-2-ylmethyl)-amino]-hexanoic    acid hydroxyamide (Compound 168179) Prepared according to General    Scheme 3.

LC-MS: t_(R)=4.1 min, m/z 375 (M+H)⁺.

-   (S)-6-[(Benzo[b]thiophen-2-ylmethyl)-amino]-2-(4-fluoro-3,5-dimethyl-benzyl)-hexanoic    acid hydroxyamide (Compound 168180) Prepared according to General    Scheme 3.

LC-MS: t_(R)=5.5 min, m/z 429 (M+H)⁺.

Additional Examples in Table 4

-   2R-(4-Chloro-benzyl)-4-{[3-(4-fluoro-3-methyl-phenyl)-propyl]-methyl-amino}-N-hydroxy-butyramide    (Compound 168150) Prepared according to General Scheme 3.-   LC/MS: t_(R)=5.3 min. MS (API-ES) m/z 407 (M+H⁺)

-   2R-(4-Chloro-benzyl)-4-{[3-(4-fluoro-3,5-dimethyl-phenyl)-propyl]-methyl-amino}-N-hydroxy-butyramide    (Compound 168156) Prepared according to General Scheme 3.-   LC/MS: t_(R)=5.7 min. MS (API-ES) m/z 421 (M+H⁺)

-   (S)-2-(4-Chloro-benzyl)-8-(4-fluoro-3-methyl-phenyl)-octanoic acid    hydroxyamide (Compound 168134) Prepared according to General Scheme    5.

LC-MS: t_(R)=10.5 min, m/z 392/394 (M+H)⁺.

-   (S)-2-(3-Chloro-4-fluoro-benzyl)-6-(4-fluoro-benzylamino)-hexanoic    acid hydroxyamide (Compound 168164) Prepared according to General    Scheme 3.

LC-MS: t_(R)=4.8 min, m/z 397 (M+H)⁺.

-   (S)-2(4-Fluoro-3,5-dimethyl-benzyl)-4    {[3-(4-fluoro-phenyl)-propyl]-methyl-amino}N-hyoxy-butyramide    (Compound 168172) Prepared according to General Scheme 3.

LC-MS: t_(R)=5.5 min, m/z 405 (M+H)⁺.

1. A compound of the formula

where R¹ is F, Cl, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons,thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF₃, OCF₃; OH, NH₂,NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CO₂H or CO₂(C₁-C₆ alkyl); m is an integerhaving the value of 1 to 3; R² is alkyl of 1-9 carbons; C₁-C₆alkylphenyl where phenyl is substituted with 0-3 R¹ groups, C₁-C₆alkylcyclohexyl, (CH₂)_(n)OR³, (CH₂)_(n)NHR⁴, NR⁴C₁-C₆alkyl,(CH₂)_(n)CF₃, CH₂OCH₂phenyl; (CH₂)_(n)NH(CH₂)_(n)R⁴, (CH₂)_(n)NR⁶R⁴,(CH₂)_(n)NR⁶(CH₂)_(n)R⁴, (CH₂)_(n)O(CH₂)_(n)R⁴, (CH₂)_(n)OR⁴, CN, phenylsubstituted with 0 to 3 R¹ groups, an alkenyl group having 2 to 9carbons and one double bond, n is an integer having the value of 1 to 8;R³ is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1to 6 carbons and the phenyl is substituted with 0-3 R¹ groups; R⁴ is H,alkyl of 1 to 10 carbons, (CH₂)_(p)cyclohexyl, C(O)alkyl of 1 to 4carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and thephenyl is substituted with 0-3 R¹ groups or with a 5 to 6 memberedheteroayl group having 1 to 2 heteroatoms selected from O, S, and N, orwith a 5 to 6 membered heteroaryl group having 1 to 2 heteroatomsselected from O, S and N and condensed with a phenylgroup, saidheteroaryl or condensed heteroaryl group itself substituted with 0-3 R¹groups, or R⁴ is C(O)(CH₂)_(p)COOH, (CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups or with a NO₂ group, or R⁴ isC(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl where the phenyl is substitutedwith 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups, or R⁴ is C(O)CH(Ph)₂,C(O)—CH₂-(3PhO—)Ph, or R⁴ is a 5 to 6 membered heteroaryl group having 1to 2 heteroatoms selected from O, S, and N, or a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenylgroup, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is CH₂heteroaryl**CH₂heteroaryl condensed with phenyl where the heteroaryl group is 5 or6 membered and has 1 to 2 heteroatoms selected from O, S said heteroarylgroup or condensed heteroaryl itself substituted with 0-3 R¹ groups, orR⁴ is SO₂-alkyl of 1 to 6 carbons, SO₂-Ph where the phenyl issubstituted with 0-3 R¹ groups or with NO₂ or with COOR⁵ group, or R⁴ isC(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkyl group has 1 to 4carbons and where the phenyl is substituted with 0-3 R¹ groups; p is aninteger having the value of 0 to 4; R⁵ is alkyl of 1 to 6 carbons orphenyl substituted with 0-3 R¹ groups or with an OPh group; R⁶ is alkylof 1 to 6 carbons; the asterisk indicates an asymmetric carbon, the wavyline represents a bond that can be in the R or in the S configuration,or a pharmaceutically acceptable salt of said compound, with the provisothat compounds selected from the group consisting of compoundsidentified below with structural formulas

are not included in the claim.
 2. A compound in accordance with claim 1where R¹ is selected independently from the group consisting of F, Cl,methyl, methoxy and phenyl.
 3. A compound in accordance with claim 2where m is an integer having the value of 2 or
 3. 4. A compound inaccordance with claim 3 where m is 2, one R¹ group is methyl in the 3(meta) position on the phenyl ring, and the other R¹ group is fluoro inthe 4 (para) position of the phenyl ring.
 5. A compound in accordancewith claim 2 where m is 3, two R¹ groups are methyl in the 3,3 (meta,meta) positions on the phenyl ring and the third R¹ group is fluoro inthe 4 (para) position of the phenyl ring.
 6. A compound of the formula

where the asterisk represents that the adjacent carbon is asymmetric andthe wavy line represents a bond which can be of either R or Sconfiguration, or a pharmaceutically acceptable salt of said compound.7. A compound of the formula

where R¹ is H or alkyl of 1 to 6 carbons; R² is H, CN, 4-Br-phenyl,alkyl of 1 to 8 carbons, alkenyl where the alkenyl group has 2 to 8carbons and one double bond, (CH₂)₄—O—CH₂-3Me-4F-phenyl or(CH₂)₆-4F-phenyl, the asterisk represents that the adjacent carbon canbe asymmetric and the wavy line represents a bond which can be of eitherR or S configuration, or a pharmaceutically acceptable salt of saidcompound.
 8. A compound in accordance with claim 7 where R¹ is H ormethyl.
 9. A compound in accordance with claim 8 where R² is H ormethyl.
 10. A compound in accordance with claim 8 where R² is4-Br-phenyl, (CH₂)₄—O—CH₂-3Me-4F-phenyl or (CH₂)₆₋₄F-phenyl,
 11. Acompound in accordance with claim 8 where R² is alkenyl.
 12. A compoundof the formula

where R¹ is H or alkyl of 1 to 6 carbons; R² is(CH₂)_(n)NR⁶(CH₂)_(p)-phenyl, (CH₂)_(n)NH(CH₂)_(p)phenyl said phenylgroups being substituted with 0 to 3 groups selected from the group F,Cl and methyl, (CH₂)_(n)NH(CH₂)_(p)cyclohexyl,(CH₂)_(n)NH(CH₂)_(p)furanyl, (CH₂)_(n)NH(CH₂)_(p)pyrazinyl,(CH₂)_(n)NH(CH₂)_(p)-2-benzo[b]thienyl said furanyl, pyrazinyl and2-benzo[b]thienyl rings being substituted with 0 to 3 R¹ groups n is aninteger having the value of 1 to 6, p is an integer having the value of0 to 4, R⁶ is alkyl of 1 to 3 carbons, the asterisk represents that theadjacent carbon can be asymmetric and the wavy line represents a bondwhich can be of either R or S configuration, or a pharmaceuticallyacceptable salt of said compound.
 13. A compound in accordance withclaim 12 where R¹ is H or methyl.
 14. A compound in accordance withclaim 13 where n is 4 and p is
 1. 15. A compound in accordance withclaim 13 where n is 4 and R⁶ is methyl.
 16. A compound selected from thegroup of compounds consisting of

or a pharmaceutically acceptable salt of said compound.
 17. A compoundof the formula

or a pharmaceutically acceptable salt of said compound.
 18. A compoundof the formula

or a pharmaceutically acceptable salt of said compound.
 19. Apharmaceutical composition for the treatment of infection by bacillusanthraci in a mammal, including a human, adapted for systemicadministration containing a pharmaceutically acceptable excipient andone or more compounds of the formula

where R¹ is F, Cl, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons,thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF₃, OCF₃; OH, NH₂,NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CO₂H or CO₂(C₁-C₆ alkyl); m is an integerhaving the value of 1 to 3; R² is alkyl of 1-9 carbons; C₁-C₆alkylphenyl where phenyl is substituted with 0-3 R¹ groups, C₁-C₆alkylcyclohexyl, (CH₂)_(n)OR³, (CH₂)_(n)NHR⁴, NR⁴C₁-C₆alkyl, (CH₂), CF₃,CH₂OCH₂-phenyl; (CH₂), NH(CH₂)_(n)R⁴, (CH₂), NR⁶R⁴,(CH₂)_(n)NR⁶(CH₂)_(n)R⁴, (CH₂), O(CH₂)_(n)R⁴, (CH₂)_(n)OR⁴, CN, phenylsubstituted with 0 to 3 R¹ groups, an alkenyl group having 2 to 9carbons and one double bond, n is an integer having the value of 1 to 8;R³ is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1to 6 carbons and the phenyl is substituted with 0-3 R¹ groups; R⁴ is H,alkyl of 1 to 10 carbons, (CH₂)_(p)cyclohexyl, C(O)alkyl of 1 to 4carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and thephenyl is substituted with 0-3 R¹ groups or with a 5 to 6 memberedheteroayl group having 1 to 2 heteroatoms selected from O, S, and N, orwith a 5 to 6 membered heteroaryl group having 1 to 2 heteroatomsselected from O, S and N and condensed with a phenylgroup, saidheteroaryl or condensed heteroaryl group itself substituted with 0-3 R¹groups, or R⁴ is C(O)(CH₂)_(p)COOH, (CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups or with a NO₂ group, or R⁴ isC(O)OC₁-C₆alkyl, or R⁴ is CH(CH₃)phenyl where the phenyl is substitutedwith 0-3 R¹ groups, or R⁴ is C(O)(CH₂)_(p)phenyl where the phenyl issubstituted with 0-3 R¹ groups, or R⁴ is C(O)CH(Ph)₂,C(O)—CH₂-(3PhO—)Ph, or R⁴ is a 5 to 6 membered heteroaryl group having 1to 2 heteroatoms selected from O, S, and N, or a 5 to 6 memberedheteroaryl group having 1 to 2 heteroatoms selected from O, S and N andcondensed with a phenylgroup, said heteroaryl or condensed heteroarylgroup itself substituted with 0-3 R¹ groups, or R⁴ is CH₂heteroaryl**CH₂heteroaryl condensed with phenyl where the heteroaryl group is 5 or6 membered and has 1 to 2 heteroatoms selected from O, S said heteroarylgroup or condensed heteroaryl itself substituted with 0-3 R¹ groups, orR⁴ is SO₂-alkyl of 1 to 6 carbons, SO₂-Ph where the phenyl issubstituted with 0-3 R¹ groups or with NO₂ or with COOR⁵ group, or R⁴ isC(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkyl group has 1 to 4carbons and where the phenyl is substituted with 0-3 R¹ groups; p is aninteger having the value of 0 to 4; R⁵ is alkyl of 1 to 6 carbons orphenyl substituted with 0-3 R¹ groups or with an OPh group; R⁶ is alkylof 1 to 6 carbons; the asterisk indicates an asymmetric carbon, the wavyline represents a bond that can be in the R or in the S configuration,or a pharmaceutically acceptable salt of said compound.
 20. A method oftreating infection of a mammal, including a human being, by bacillusanthraci by administering to said mammal a pharmaceutical compositioncontaining a pharmaceutically acceptable excipient and one or morecompounds defined in claim
 19. 21. A method of inhibiting the lethalfactor enzyme released by bacillus anthraci where such inhibition isneeded, said method comprising contacting said enzyme with one or morecompounds defined in claim
 19. 22. A method in accordance with claim 21where said contacting comprises administering to a human being infectedby bacillus anthraci a pharmaceutical composition containing apharmaceutically acceptable excipient and one or more compounds definedin claim 19.